Endothelial cells (EC) are major participants in chronic and acute inflammation. They regulate the passage of cells and fluids between the bloodstream and the extravascular space. In addition, they respond to inflammatory stimuli by secreting factors which have a variety of effects on hematopoiesis (Quesenberry and Gimbrone, Blood. 56: 1060-1067, 1980), chemotaxis (Streiter et al, Science, 243: 1467-1469, 1989), and coagulation (Bevilacqua et al, J. Exp. Med., 160: 618-623, 1984). Interleukin 1 (IL-1) is secreted by a wide range of cell types as an almost universal response of cells to injury (Neta and Oppenheim, Ann. Int. Med. 109: 1-31, 1988). Many cell types secrete this factor under appropriate stimulation, and many cell types respond, and in a variety of ways. IL-1 is found at sites of inflammation, and when injected as a purified protein, results in erythema and an influx of granulocytes from the bloodstream and secondarily, tissue destruction (Beck et al, J. Immunol., 136: 3025-3031, 1986: Pettipher et al. Proc. Nat'l. Acad. Sci., 83: 8749-8753, 1986).
Several laboratories have shown that endothelial cells have a rapid response to IL-1 which is consistent with their accessory nature in the inflammatory reaction. Two of the best described responses are an increase in procoagulant activity (Bevilacqua et al. 1984, supra) and a concomitant increase in adhesive capacity for leucocytes (Bevilacqua et al. J. Clin. Invest., 76: 2003-2011, 1985).
As the lining of blood vessels, endothelial cells are uniquely positioned to regulate the traffic in inflammatory cells and their reactive by-products. In addition, endothelial cells can themselves secrete into the bloodstream newly synthesized proteins which may be an early indicator of the inflammatory process. Despite this key role, very few therapeutic approaches or diagnostic indicators have been developed that directly address the role of this cell type. The biology of endothelial cells is starting to be understood now in much better detail due to the recent success in culturing these cells in the laboratory.
As mentioned above, a key mediator of the inflammatory response is IL-1. IL-1 is a 17 Kd polypeptide secreted by macrophages and many other cell types which is capable of eliciting a wide array of responses ranging from induction of fever, to proliferation of inflammatory cells and the recruitment of mature leucocytes from precursors in the bone marrow (reviewed by Dinarello, FASEB J., 2: 106-115, 1988).
Endothelial cells both respond to and secrete IL-1 at a very early stage of the inflammatory process. While a byproduct of bacterial infection with gram negative organisms is the production of endotoxin and the consequent secondary production of IL-1,the issue of whether mechanical injury can trigger IL-1 release is a critical but as yet unanswered question for students of sports-induced inflammation.
It is believed, based upon work by several laboratories in the past decade, that the binding of leucocytes to the vascular wall, a process that can be mimicked in vitro with IL-1 treatment of endothelial cells, is the first step in the diapedesis of leucocytes into the tissue space. However, several aspects of this process, especially as they may be related to the utility of current anti-inflammatory agents for intervention, remain unclear.
IL-1 induces a rapid alteration in the membrane properties of cultured human endothelial cells. This is evident from the ability of treated cells to bind leucocytes, their acquisition of procoagulant activity and the expression of new cell surface antigens including some for which no functional property has yet been assigned. In those cases studied, the development of the new properties described is sensitive to the action of actinomycin D and cycloheximide, suggesting a requirement for the synthesis of new message and new proteins.
Binding of leucocytes to basal and activated endothelial cells has been studied by several laboratories. Evidence has been presented that granulocytes, monocytes T-, B- and NK cells all can bind to endothelial cells after stimulation with very low concentrations of IL-1, on the order of 10.sup.-10 M. The suggestion has been made that more than 1 endothelial cell membrane protein is involved in the adhesion process. Two laboratories have presented evidence in the case of granulocytes that the 90 Kd protein termed intercellular adhesion molecule (ICAM) as well as the 115 Kd molecule termed endothelial leucocyte adhesion molecule (ELAM) contribute to cytokine induced adhesion. Nonetheless, the role of these and other molecules in the binding of mononuclear cells remains to be clarified.